2006 Fiscal Year Final Research Report Summary
Studies on the synthesis of extremely potent antitumor hybride steroidal dimer
| Project/Area Number |
16590018
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Hoshi University |
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Principal Investigator |
TSUBUKI Masayoshi Hoshi University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (90163865)
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| Project Period (FY) |
2004 – 2006
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| Keywords | cephalostatin / OSW-1 / Wittig rearrangement / allyloxymalonate / thiophene / thiazole |
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| Research Abstract |
Wittig rearrangement has been established as one of the most useful synthetic tools in organic synthesis. Considerable variation in Wittig rearrangement has been explored and widely applied to natural product synthesis. In a continuation of these efforts, we were interested in the development of Wittig rearrangement under neutral condition. We considered the possibility that a-allyloxymalonates undergo [2,3]-sigmatropic rearrangement under the Krapcho reaction condition. Treatment of dimethyl a-allyloxymalonates with lithium chloride in HMPA at 130-140℃ for 5-30 min resulted in sequential Wittig rearrangement and demethoxycarbonylation. This afforded methyl 2-hydroxy-4-pentenoate derivatives in 55-96% yields with high E selectivity. Its application to steroidal side chain synthesis was also carried out. Sequential Wittig rearrangement and demethoxycarbonylation of (E)-17(20)-pregnen-16a-yloxymalonate furnished (20S,22S)-and (20S,20R)-22-hydroxy steroids in a ratio of 76:24, respectively. Major isomer, (20S,22S)-steroid, could be a key intermediate for the synthesis of biologically active ecdysteroid, withanolide, OSW-1, and cephalostatin.
We have accomplished the synthesis of an extremely potent antitumor saponin OSW-1 and its analogues by means of the Wittig rearrangement of allylic thiophenemethyl ether for the construction of (20S)-22-hydroxy steroidal side chain. Thus, Wittig rearrangement of 17E(20)-ethylidene-16α-thiophenemethyloxy steroid, prepared from commercially available epoxy ketone, afforded (20S)-22-hydroxy steroid in 59% yield. Introduction of trans diol functionality at the C(16) and C(17) positions was carried out by usual methods to give 16β,17α-diol. Glycosylation of the accepter with disaccharide imidate, synthesized by the known protocol, proceeded smoothly under the promotion of TMSOTf to give the desired β-glycoside. Removal of all protecting groups followed by desulphurization furnished OSW-1.
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